The present invention relates to a novel C1-phosphate analogue of uridine-5′-diphosphate (UDP)-GlcNAc effective as an OGT (O-linked N-acetylglucosamine (O-GlcNAc) transferase) inhibitor, and a preparation method thereof.
As for the post-transcriptional modification of proteins by O-GlcNAc, the hydroxyl moiety of serine or threonine residues at nuclear or cytosolic proteins in eukaryotic cells is modified into one O-linked β-N-acetylglucosamine. The modification occurs in all kinds of eukaryotic cells from yeast to human.
Several scores of O-GlcNAc-modified proteins have been identified for twenty years after the discovery of O-GlcNAc, proving that O-GlcNAc has an important role in the cell regulation mechanisms, including transcription, translation, cell signaling, protein stability, nuclear localization, and so forth.
Beginning from nuclear pore proteins, a variety of proteins modified by O-GlcNAc have also been identified, including cytoskeletal proteins and their related regulatory proteins, viral proteins, nuclear proteins, tumor suppressor, nuclear oncogene proteins, catalytic subunits of RNA polymerase II, and many transcription factors. There is no interrelationship between these O-GlcNAc-modified proteins, but one thing in common is that they are all phosphoproteins. Most of the O-GlcNAc-modified proteins are known to assemble into highly controlled multimeric forms, which are, in many cases, regulated by post-translational modification.
It is discovered that O-GlcNAc metabolism/modification is closely related with various human diseases, such as diabetes, degenerative brain diseases, neurogenic brain diseases, cancers, etc.
The enzyme that enacts the transfer of GlcNAc is O-GlcNAc transferase (OGT), and the donor substrate is uridine-5′-diphosphate (UDP)-GlcNAc. For more studies on the biological functions of O-GlcNAc and the molecular-scale structure of OGT, it is necessary to search for substances suitable for effective inhibition of OGT. However, there is still no well known substance that displays an OGT inhibitory effect.
It is therefore necessary to develop a novel UDP-GlcNAc analogue as a novel inhibitor for O-GlcNAc transferase (OGT).